Theoretical Study of Catalytic Efficiency of a Diels–Alderase Catalytic Antibody: An Indirect Effect Produced During the Maturation Process
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Other documents of the author: Martí Forés, Sergio; Andres, Juan; Moliner, Vicent; Silla, Estanislao
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Show full item recordcomunitat-uji-handle:10234/9
comunitat-uji-handle2:10234/7013
comunitat-uji-handle3:10234/8638
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http://dx.doi.org/10.1002/chem.200700290 |
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Title
Theoretical Study of Catalytic Efficiency of a Diels–Alderase Catalytic Antibody: An Indirect Effect Produced During the Maturation ProcessDate
2008-01Publisher
WileyISSN
0947-6539Bibliographic citation
Chemistry - A European Journal, 14, 2, p. 596-602Type
info:eu-repo/semantics/articlePublisher version
http://onlinelibrary.wiley.com/doi/10.1002/chem.200700290/fullVersion
info:eu-repo/semantics/publishedVersionSubject
Abstract
The Diels–Alder reaction is one of the most important and versatile transformations available to organic chemists for the construction of complex natural products, therapeutics agents, and synthetic materials. Given ... [+]
The Diels–Alder reaction is one of the most important and versatile transformations available to organic chemists for the construction of complex natural products, therapeutics agents, and synthetic materials. Given the lack of efficient enzymes capable of catalyzing this kind of reaction, it is of interest to ask whether a biological catalyst could be designed from an antibody-combining site. In the present work, a theoretical study of the different behavior of a germline catalytic antibody (CA) and its matured form, 39 A-11, that catalyze a Diels–Alder reaction has been carried out. A free-energy perturbation technique based on a hybrid quantum-mechanics/molecular-mechanics scheme, together with internal energy minimizations, has allowed free-energy profiles to be obtained for both CAs. The profiles show a smaller barrier for the matured form, which is in agreement with the experimental observation. Free-energy profiles were obtained with this methodology, thereby avoiding the much more demanding two-dimensional calculations of the energy surfaces that are normally required to study this kind of reaction. Structural analysis and energy evaluations of substrate–protein interactions have been performed from averaged structures, which allows understanding of how the single mutations carried out during the maturation process can be responsible for the observed fourfold enhancement of the catalytic rate constant. The conclusion is that the mutation effect in this studied germline CA produces a complex indirect effect through coupled movements of the backbone of the protein and the substrate. [-]
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